2-phenylquinoline-3-aryl carbamates



United States Patent 2-PHIENYLQUINOLlNE-3-ARYL CARBAMA-TES Frank J. Kreysa, Richmond Hill, N. Y., assignor to Cherno Puro Manufacturing Corporation, Long island (City, N. Y., a corporation of New York No Drawing. Original application October 39, 1952, Serial No. 317,820. Divided and this application December 16, 1953, Serial No. 405,233

fClaims. (Cl. 260-287) The present invention relates to antidiuretics and more .particularlyiothe iSYIlthCSlS 'of new derivatives of 3-hydroXy-2-phenylcinchoninic acid (HPC) and thecarboxylic .acid derivative 3-hydroXy 2-phenylquinoline-4,8-dicar- ,bOXYliC acid. This is a division of my co-pending application Ser.'N0. 317,820,-filed October 30, 1952, and now abandoned.

.duces .a decreasepin'zurine'volume or diuresis after water has been administered.

vSimilarlyeit is :of interest 'to note that 3-hydroxy-2- vphenylcinchoniniciacid'now called by many investigators HPC, has.a carboxyliciderivative which is much more powerful .in its .antidiuretic effect. called r3=hydroxyt2-phenylquinoline-4,8 dicarboxylic acid.

This compound is Ordinarilyyitsuse is somewhat limited due to the difficultynandexpense :in the preparation of one of its reactant "materials, namely 2,3 diketoindoline-7-carboxylic acid, (isatin-7-carboxylic acid), which when condensed withsphenacyl acetate 'gives the desired'product.

The antidiuretic'activity-of these cinchoninic acid derivatives has'been especially found to be'useful in cases ofdiabetes insipidus. "In the disease known as diabetes insipidusthe patient passes larger quantities of watery dilute urine and sufiiers-very intense thirst as a consequence. Clinical studies of-HPC and"3-hydroxy-2-phenylquinoline- 4,8-dicarboxylic acid have fur'ther revealed'that these compounds reducewateroutput in casesof'hurnan diabetes insipidus. It has also been known that HPC and the 8- carboxylic derivatives: ofaHPC. affect the water output in diabetes insipidus, not by direct action on the water reabsorbing element in the tubules of the'kidney, but rather by mediation of HPC on thepituitary system in the production of the antidiuretic hormone therein.

HPC has also been testedforits effect on renal secretion of phenol red and penicillin. .It was found that HPC inhibits the secretion by therenal tubule of phenol red and penicillin. The implication of this efiect is obvious, in that certain diseases necessitate that the above compounds remain at the site ofaction so as to function best.

It is known thatHPC reduces theascorbic acid content of the rat adrenal gland when ;the anterior pituitary is present and also that HPCincreases the excretion of uric acid from the blood. These facts suggested that HPC-might be effective in diseases which respond to ACTH. HPC-was therefore tested for its efiects in acute rheumatic fever and chronic rheumatoid arthritis.

The eifect of HPC upon fever and arthritis on 10 patients with rheumatic fever was dramatic. The fever was'shown to subside immediately or in some patients within'6 hours. Asforarthritis associated with rheu- 2,749,347 Patented June 5, 1956 ice matic fever, tenderness and joint pain wererelievedlin all I instances about as rapidly. as the feven'butithe ,ob-

'jective signs of swelling persistedLin,some for.about 24 hours. Of the. IOpatients treated withHBC for,,"rheumapituitary. or adrenal cortical hormones.

in theflatestpaper ,onjHPQlager. (,BulL, JohnsrHopkins'JI-Iosp. .(Feb. 1952), ,,p. .121), has shown that LHPC has the ability to stimulate the. a'drenahgland by way of .the pituitary. 'Hefurther listsits .toXic reactions, which .are. present in. about 20% of thepatientstested. j'Hejtlso shows that'I-IPC has a high protein binding.,property.with albumin.

Since the side. effects of, the drug are nausea,.v0.miting,

dmg'fever, and abdominal cramps, itlisato benoteldeat this point that thetoxicity of }HP.C.-an'd .3'-hydroXy.-2-

phenylquinoline-4,S dicarbQXyIicacid is significant enough soas to warrant further investigation,intdmodificationof its structures. However, in the modification of their structures it is important that, there. be ,no. radical. change from their basic structures, but rather. .arrrodification: that would help'cut down toxicity, perhaps by ,slowenabsorption, and yet retain all the "beneficial ,iefiects ,associated with HPC.

Accordingly, it is aprirnary. object of fthe present invention to synthesize new derivatives ,ofHPCand its S-carboxylic acid derivative wherein the toxicreactions are substantially eliminatedor of anegligible nature.

"A secondary objectof 'thepresent invention vwasto determine .what group or groups, .orlthe .hydrcXYwthe carboxylic, .and the phenylrgroups,v in the ,quinolinenucleus. is or are absolutely.essentialvin. the ,production. of

the antidiuretic effect.

A further object of thepresent,invention,. after.the

determination of the groupongroups fromthe'foregoing pared. IMarshall and Blanchard (l. ,JPharmacolLnnd 'Exper. Therap.,.vol (1949), p. established in-a series'of'tests that the hydroxy grou inposition No. 3 is absolutely required forjthe antidiureticcffect. These investigators tested various isomers, andhomologues of HPC.

Inasmuch as the data of Marshall, .Blanchardand Dearborn (BulL, John Hopkins Hospital, .vol. 8. 6,. No. ,2 (Feb. 1950), p. 90), established .the factnthat the hydroxy;group of the cinchoninic acid series had-to. belin position'No. 3, the problem of synthesizing newt-.derivatives resolved itself intonmaintaining ,the '3 l1ydroxy group and modifying either the ,carboxylic, .the phenyl ,or the tertiary amino group. Since the vcarboxylicgroup is much more reactive it was decided to. prepare deriva- "tivesof thev acid of HPC and 3-hydroxy:2+phenylquinoline- 4 ,8 dicarboxylic acid. Thus, the derivatives, oncepre- ,pared, ,and if administered, had to fulfillthe requirements of complete reversion to be the mother compound (either to HPC or 3-hydroxy-2-phenylquinoline-4,8-dicarboxylic acid), have good solubility, slow absorption and diminished toxic effect in the body. The preparations of the esters of the carboxylic group seemed to fit the requirements best. Since HPC and its 8 carboxylic acid derivative, when given by month are absorbed by the intestine which has an alkaline pH, it was conceived that the esters would be slowly saponified to the alkaline acid salt and the free alcohol. Also it was assumed that since the saponification by the intestine is slow, the toxicity of the free acid would be diminished in intensity if not completely, and that its effects would last over a longer period of time. As far as the problem of toxicity of the alcohols liberated from the esters are concerned, they would be either oxidized to the corresponding acids or to CO2 and water by the body. If the alcohols reverted to the corresponding fatty acids, instead of CO2 and water, it would be noted that the toxicity of the nor mal fatty acids decreases gradually from C1 to C and then increases rapidly to C9. Therefore it was decided to prepare the low carbon ester series of HPC and 3- hydroxy-2-phenylquinoline-4,8-dicarboxylic acid.

Another problem existed with regard to the preparation and methods to be employed in the synthesis of urethane derivatives of 3-hydroxy-2-phenylquinoline.

Since the 3-hydroxy position of the 2-phenyl-cinchoninic acid has previously been shown to be the group that effected biological activity most, it was considered that the preparation of various carbamates by the action of various aryl isocyanates on the phenolic group might prove to be of possible worth in cancer theraphy. Inasmuch as the carboxylic group might prove to be an interfering constituent in the preparation of these urethanes, the compound HPC was first decarboxylated, and then reacted with different isocyanates.

As has been shown by previous investigators, urethane (ethyl carbamate) NH2COOC2H5 has an inhibiting effect on certain cancerous tissues. It has been shown that in hanging drop cultures of fibrocytes 0.1-0.5 of urethane first stimulated then retarded cell mitosis. Another investigator has shown that urethane has an inhibiting action on leukemia. Still others have shown that in the chemotheraphy of leukemia on mice with radioactive carbonyl-labeled urethane, that the mice with advanced lymphoid leukemia and also mice with mammary carcinoma, retained more radioactivity 24 hours after injection than normal mice, and that cellular growth was somewhat diminished. These facts, in addition to a tremendous amount of material in the literature on carbamates and their derivatives as possible cancer inhibitors, has led me to synthesize some urethane derivatives of 2-phenyl-3-hydroxyquinoline. The foregoing is suggestive rather than exhaustive of the possible uses in medicine of the various derivatives to be produced.

In the method of Hanns and Frankel (J. Prakt. Chenr. vol. 133 (1932), pp. 259-72) the preparation of 3- hydroxy-Z-phenylcinchoninic acid involved the use of phenacyl bromide. In following this method it was found that the yield was so low as to be impractical in preparing a large batch. Accordingly, phenacyl acetate was used instead of phenacyl bromide, by which Marshall and Blanchard (J. Pharmacol. and Exper. Therap., vol. 95 (1949), pp. 18590) reported a yield of 82%. Due to the fact that phenacyl bromide is relatively less expensive than phenacyl acetate, the latter was prepared according to the method of Cebrain (Anales real. Soc. espon. fis. y quin., vol. 44, Ser. B (1948), p. 587) as follows:

To 120 gm. of phenacyl bromide dissolved in 400 cc. of hot ethyl alcohol was added, contained in a one liter beaker, a saturated alcoholic solution of 64 gm. of fused sodium acetate. The solution was then allowed to stand 24 hours at room temperature. The precipitated sodium bromide was filtered, and the filtrate was heated on a water bath in order to remove the ethyl alcohol. The solution, when evaporated to about 150 cc., was poured into 200 cc. water so as to dissolve any excess sodium acetate and sodium bromide. The solution was chilled, and the phenacyl acetate solidified. The solidified phenacyl acetate was then recrystallized from ligroin and white flat crystals separated which were filtered and dried in a dessicator over paraffin and sulfuric acid. The melting point was 50' C. and the yield as 79%.

3-hydroxy-2-phenylcinchoninic acid was thereafter prepared as follows:

The minimal quantity of solution of 42 gm. of 97.7% sodium hydroxide in cc. of water necessary to effect solution was added to a suspension of 36.7 gm. (0.25 mole) of isatin in 300 cc. of Water contained in a 3 liter flask. To the solution obtained, was added first, a solu tion of 45.4 gm. (0.25 mole) of phenacyl acetate in 250 cc. of warm ethanol and then the remainder of the solution of sodium hydroxide. The mixture was refluxed over a free flame for 3 hours and allowed to remain at room temperature overnight. It was then diluted with 700 cc. of water and filtered to remove some tarry material. To the filtrate, with constant stirring there was added in order, 83 cc. of concentrated hydrochloric acid and 28 cc. of glacial acetic acid. After remaining at room temperature overnight, the precipitated product was collected upon a mm. Buckner funnel washed with four 50 cc. portions of cold water and transferred to a 3 liter beaker containing 900 cc. of water. The solid was brought into solution by the addition of 20 cc. of 28% ammonia water and filtered from a slight amount of insoluble material. To the filtrate 50 cc. of 6 N acetic acid was added and, after several hours at room temperature, the product was separated by filtration, washed with four 75 cc. portions of water, dried at room temperature for a week, and then at 60 until constant weight was attained. The reason that the acid was first dried at room temperature was that the compound formed unstable hydrates which lost water quite readily at room temperature. If the compound was dried in an oven without preliminary air drying, evidence of partial decomposition was detectable. The yield was 52.l gm. (78.9% of theoretical) of deep yellow microcrystalline product, melting point 2067 C. with decomposition.

NaOH NH:

Preparation of n-alkyl ester derivatives of B-hydroxy-Z- phenylcinchoninic acid METHYL3AHYDROXY-Z-PHENYLCINCHONINATE acid. The solution -=was made alkaline-"with-ammonia water, and with the change in pH the yellow solid Went into solution. .Extrac't-ion was then carried-.ouvwith three 20 cc. portions of ethyl ether. The ethensolution was Washed with 10 cc. Water with subsequent-separation from the ether layer. 'Drying of the ether solution over anhydrous potassium carbonate was continued for30 minutes and decanted from the solid potassium carbonate. The ether solution was then evaporated over a hot-waten'bath to a volume. of.10.cc. iCrystallization-set-in after several hours giving .8 gm. of long light yellow needles Whose melting point was 104-5 C., corrected. *The yield was 38.1%. of .theoretical.

Analysis.-Calculated for. C1'7H13N1Os:

Theory: Found:

C=73.09% C=72.93% H: 4.69% H: 4.75% N: 5.02% N: 4.91%

i Preparation ofelhyl 3-hydroxy 2 phenylcinchoninate IIntoia dry l25 cc. Erlenmeyer flask containing 10 cc. of absolute. ethanol (.2.mole) ,was .added.2.0. gm. (.006 mole) of.3-hydroxyr2-phenylcinchoninic acid .and 0.6,.cc...of con- ,centratedsulfuric acid. :Themixture was thenheated un'dera reflux over asteamibathfor. 5. hours. At the. end ofhalf-an hour,.the.acidlhad completelydissolved giving a brown solution. The solution was then. cooled and to it .was. added'30cc. or. cold water. A slightamountofyel- .low precipitate settled out as well assome oil, whichhardened to abrown solidupon shaking. Ammonia .wateriwas then added to the solution until itwas alkaline to pH paper. Extraction wasthen carriedout=with .three 25cc. portions of ethyl ether. The ether layer was then Washed with 10 cc. of cold Water, separated from the water layer, dried over anhydrous potassium carbonate for 30 minutes, and then-decanted from the solidpotass'ium carbonate. Then the "ether solution was evaporated to a volume of 10 cc. on. a .water bath. Crystallizationset in after 24 hours giving 19 gm. long lemon yellow needles whosemelting point was 110-1l1 .C., corrected. The yieldwas 40.9% of theoretical.

. Analysis.-Calculated for C-1BH15N103I "Theory: Found:

C=73.71% C='73.94% I I= 5.15% H: 4.99% N: 4.71% N: 4.80%

. +OH HzOH a (IJOOCHzCH:

6 Preparation 10f ethyl-'3-hydroxy-2'rphenylcinchoninate from silversalt and ethyl bromide To .2 gm. of silver-3-phenylcinchoninate and 2 cc.=of

- dry ethyl bromide suspended in 50cc. of dry =benzine, in

a 200 cc. heaker,- there was placedw-a stirrer, which was rotated for two hours. The: silver salt did not seem to react, and so the solution wastransferredto a.1-50-..cc.

fiask equipped with: a. reflux, condenser. and. heated for.;2

hours. :Thissolutionwas allowed to;stand;overnight. :The solutionv was filteredsand the filtrate/wasidistilled. teat-final volume of;about. 10 cc. 'Thefiltratewasthenaallowed to stand over-3a.cc.:ofwater f0r1a 'few days. :Longdightryl- .low crystals formedandthese were :filtered zandzgdried.

This .gave '07 .gms. (43-.8% 10f. theoretical) of Tethyl S- hydroxy-2-phenylcinchoninate :meltingaat :..C., :cor-

rected. This compound was identical withtheiethyli ester preparedby the sulfuric acidmethod.

Analysis.-Calculated. for CisHis'NiOaz ('10 OCHaCH:

, AgBr Q Preparation of n-propyl-3-hydr0xy-2-phenylcinch0ninate To a dry cc. Erlenmeyer flask containing 15 cc. of redistilled n-propanol (.3 mole) and .7 cor-of concentrated sulfuric acid was added. 2.0 grn.- (.006 mole) of 3-hydroXy-2-phenylcinchoninic acid. 'The solution turned, after heating 4 hours on a steam bath, to dark brown, but there still wasmuch undissolved acid on the bottom of the flask. Since the reaction was not proceeding well, in that the acid did'not dissolve, or that refluxing seemed evident, the steambath Was discarded and a direct weak flame used .in its place. .The heating was continued for two hours, and the solution cooled. 30 cc. of cold water was added to the sOlutionandWhen made'alkalinewith ammonia water. iExtraction was accomplishedrbythree .25 cc. portions of ether,.-and the; ether solution-was-dried for 30 minutes over .anhydrous potassium :carbonate. After decanting. the ether-solution from the solid'ipotassiurnsalt, the ether was evaporated onahot-waterbath toafinal volume of 20cc. .The filtrate was allowedto ,stand overnight, givingll gm. of .pale yellow'needles,

melting at 75.3-75.5 C., corrected. The yield'was 47.8% of theoretical.

Analysis.-Calculated for C1QH17N'1O3:

Preparation of n-butyl-3-Izydr0xy-2-phenylcinchonirzate 2 gm. of 3-hydroxy-2-phenylcinchoninic acid (.006 mole) were added to a dry 125 ml. Erlenmeyer fiask containing cc. of n-butanol (.2 mole) and .8 gm. of concentrated sulfuric acid. The mixture was then heated on a water bath under reflux for 8 hours, giving a dark brown solution. The solution was cooled, diluted with 30 cc. of cold water, and made alkaline with ammonia water. Extraction was carried out with three 25 cc. portions of ether, which was subsequently washed with 10 cc. of cold water, and dried over anhydrous potassium carbonate. Evaporation of the ether followed decantation from the potassium carbonate solid, and after 24 hours of standing, no crystalline growth was observed. Since it was assumed that the ester was highly soluble in the butanol (extracted by the ether also) the complete solution was brought down to dryness on the steam bath. Before performing this operation however, /2 gm. of charcoal (Darco) was added to the solution and then filtered. It also was found that the addition of water to the filtrate would not: precipitate the ester, since the solution was insoluble in water and 2 layers formed. To the residue was added cc. of ethanol, and the mixture was heated to boiling in order to dissolve it. Solution was effected, and the brown alcoholic solution filtered. One cc. of water was added to the filtrate and a slight turbidity resulted. The solution was allowed to stand 24 hours and 0.69 gm. of light yellow crystals formed. Recrystallization was from acetone and alcohol (1:1) giving needles that melted at 74.5 C., corrected. The yield was 29.1% of theoretical.

AnaIysis.-Calculated for C20H19N1O3:

Theory: Found:

C=74.76% C=74.89% H: 5.96% H: 6.03% N: 4.36% N: 4.29%

(IJOOH CHzCHzCHnCHzOH @itb Preparation of n-amyl-3-hydr0xy-2-phenylcinchoninate Into a 125 cc. Erlenmeyer fiask containing 2 gm. (.006 mole) of 3-hydroxy-Z-phenylcinchoninic acid and 15 cc. (.3 mole) of n-amyl alcohol (l-pentanol) was added .7 gm. of concentrated sulfuric acid. The mixture was refluxed over a steam bath for 3 hours. Since after the 3 hours the mixture did not go completely into solution, the steam bath was discarded and a direct weak flame used in its place. The heating was continued for an additional 3 hours. Then the flask was cooled and diluted with 30 cc. of cold water. This gave an oily layer and some yellow crystals settled out. When the mixture was made alkaline however, the yellow solid dissolved. The solution was extracted with three 25 cc. portions of ether and washed with 10 cc. of cold water. Drying of the ether layer was made over anhydrous potassium carbonate for minutes. The ether solution was then evaporated to dryness on a steam bath. Ethyl alcohol was used to dissolve the residue, and then filtered. Some yellow solid remained undissolved and its melting point was found to be 203.

This is probably the unreacted 3-hydroxy-2-phenylcinchoninic acid which has a melting point of 206-7". The dark filtrate was treated with .1 gm. of activated charcoal (Darco) and filtered. The filtrate, which had a total volume of about 15 cc., was then allowed to stand overnight and .7 gm. of light yellow needles settled out. Re-

crystallization was from ethyl alcohol which gave needles that melted at 73.5 74.0 C., corrected. The yield was 24.1% of theoretical.

Analysis.Calculated for C21H21N1O3:

Preparation of silver-3-hydroxy-2-phenylcinchoninate Initially, when esterification was attemped with hydrochloric acid as catalyst, instead of sulfuric acid, all attempts at preparing the esters failed. This fact cannot be explained except in assuming that the precent of HCl by weight to the alcohol was not sufficient so as to catalyze the reaction. The silver salts of the acids were therefore prepared in the hope that the reaction of the salt with the alkyl halide might prove more satisfactory in the preparing of esters.

To 2 gm. (.006 mole) of 3-hydroxy-2-phenylcinchoninic acid was added 40 cc. of water. The acid was then carefully neutralized by adding 1 cc. of concentrated ammonium hydroxide in 30 ml. of water which completely dissolved the acid. Then .3 gm. (slight excess) of silver nitrate dissolved in 30 ml. of water was added to the solution with vigorous stirring. Immediate precipitation occurred giving a heavy yellow precipitate. This was filtered and washed with cold water, until the wash solution gave a negative test with dilute hydrochloric acid. The salt was dried in the dark at room temperature in a desiccator over sulfuric acid. The yield was 2.1 gm. (75.0% of theoretical) of light brown fine crystalline salt which melted at 221.5 C., corrected, with decomposition.

Analysis-Calculated for CisHmOsNiAg:

Theory: Found:

C=5l.61% C=5l.60% H: 2.71% H: 2.62% Ag=29.00% Ag=28.87%

Preparation of the 2,3-diket0ind0line-7-carboxylic acid Methyl anthranilate was first prepared according to the method outlined by Beilstein (vol. 14, pp. 3l7, 53!), and recrystallizing the same as taught by Long, U. S. Patent No. 2,517,691, August 8, 1950. Methyl isonitrosoacetoanthranilate was prepared from the methyl anthranilate by following the procedure of Waldman (J. Prakt. Chem., vol. 147 (1937), p. 338).

2,3-diketoindoline-7-carboxylic methyl ester was then prepared as follows:

Into 190 gm. of concentrated sulfuric acid, which was heated to 70 C., was slowly added, under strong agitation, 38 gm. of methyl isonitrosoacetoanthranilate in small portions, so that the temperature did not exceed C. After complete solution of the solid, which gave a dark red color, the reaction mixture was heated for 10 minutes at C. After cooling, the mixture was poured into 800 ml. of water and a brown precipitate formed. This was filtered, washed with three portions of 20 ml. of water and dried. 34.1 gm. of light brown crystals were collected and melted at 192 C., with decomposition.

Since Waldman (J..Prakt. .Chem., :vol. '147, (1937), p. 338) reporteda meltingpoint of 192.C..-also, theicompound was not, recrystallized. The yield.-.was.9,7'-.3% of theoretical.

Isolation of 2,3-diketoindoline-8-carboxylic.. acid was then effected as follows:

Into a 1000 ml. 3 necked flask equippedwithastirrer and a reflux condenserwas added 34 gm. of isatin-S-carboxylic methyl ester and 400 cc. of 7.5%=:.alcoholic potassium hydroxide. This mixture was -then refluxed 5 hours, during which time much dark yellow solid .came out ofsolution. The.-.alcoholic solution was then evaporated on a steam bath, giving a final volume of about 50 ml. and the mixture was acidified with concentrated .hydrqcbloric acid. The solution turned from yellow tOi orange and the precipitate was filtered oif. The still wet precipitate was-then treated with cold sodium bicarbonate solution until the solution \waslalkaline to pH paper. This operation was carried .out so as .to dissolve the isatinflcarboxylic acid from the unhydrolyzed methyl ester. The

orange colored solution wasfiltered, leaving a slight yelzlow-residue. The vacidwas then isolated from the filtrate byracidification with hydrochloric acid. Recrystallization .:was accomplished'from23- liters of. water giving-large-orange pflatccrystals: melting 31112725 C. The yield of isatin 7- .carboxylic :acid was 29.3 gm. (93.0%:of theoretical).

Preparation of 3 hydroxy-2 phenylqain0line4,8=a'icarboxylic acid :In the preparation :of thisfiicarboxylic acid derivative, tthermethod .nsed. .is=:that ,o'fZMarshall :et:= a1. (BulL, Johns HopkinmHospital, vol.':'86,.=No. '2. (:Feb. .19510),-p.95). T0; a'.S01lltl0I1.0f 32 gm. ('0; 18: mole); ofphenacylaacetate :'in.100 cc. .of warm ethanol was added .,:a solutionuof 18.7 gm. (0.15 mole) of a2,3=diketoindoline'iecarboxylic :acid in ;l50.1 cc. of F6 N sodium. hydroxide gcontained in .a 500.cc.;flask. :The anixtureawasrthen. gently refluxed for hours, "left atzzroom xternperature eovernight and diluted with -300.cc.- of water. Following rernovalof the ethanol hy..distillation, the mixture was-diluted with Water to a-volume of. approximately l liter. andfiltered through a bed of glasswool to remove tarry by-products. The filtrate was treatedWith- 1'50-cc.- of 6 N-hydrochloric .acid. and ,left .at roorndemperature for-3 ,hours. The ;precipitated product was .collected, ;washed -Wl1h water, and. dissolved :in a =mi-xture of 75.00 cc. ;-of Warm water and cc. .ot:6N;.ammonia.-Water. ;The*resultin 'g solution was stirred .with decolorizing carbon (:3 ;gm. ;Dar.co), filtered, precipitatedby the dropwise'addition' of 30 cc. of-.:6 N-hydrochloric acid andJeft at;-room temperature overnight. The precipitated product -Was collected, washed with five 10 cc. portions of -.water ,and.:dried at 37C. for 3 days. The .dry..product wasgpulverized, boiledzfor a few minutes .with 50cc. of ethanol, separated from the solvent by filtration, washed: with ethanol :and,.dried,yfirst in an evacuated desiccator over sulfuric acid -for 24 hours and then at 105 C. .for .2 hours. .Yield .was 26.1 gm. (83.2% .of theoretical) -,.of pale .yellow-product. Upon taking. its M.. P., the color began .to darken at 270 C. becoming progressively darker as ,the temperature was:raised to 305 .C. when @the dark mass melted, with decomposition.

Preparation of-di-n-alkyl esters of 3-hydroxy-2-phenylquinoline-4;8-dicarb0xylic acid.

'DIMETHYL-3-HYDROXY-2-PHENYLQUINOLINE- 4,8-DI CARBOXYLATE Into a 125 --ml. dry "Erlenmeyer flask containing 1 .gm. of 3.-hydroxy92 phenylquinoline-4,8-dicarboxylic .acid (.003 mole), and'lO cc. of absolute methanol (.2 mole) was added .5 cc. of concentrated sulfuric acid. =The,solution was thenrefluxed for .6 hours undera steam bath .and then cooled. To thedark brown solution .was added ,30 ml. of cold water. This operation .gave-an oily layer, with some ;yellow crystals settling :',Ql1t. .However,. as -soon as the solution-Was made alka- .line withammonium hydroxidetthe "yellow crystals :dissolved. The solution was then :extracted with three 25 ml. portions of ether, .andthe extract-was washed -with '10 .;ml. of cold water, and :dried over anhydrous ..potassium carbonate. The decanted-ether solution was .,then evaporated on ;a hot-water bath to 10 ml. The solution, after'several hours, .;gave .5 gm. (45.5% of rtheoretical) of..orange crystals-whichmelted alt-118.5 C.-corrected,--when' recrystallized from ethanol.

Analysis.Calculatedv for C19H15N1'O5:

Theory: Found:

1 C: 67.65 C='67.-60% V H-='4.47% H=4-.62% 'N=4;15% N=4.20%

(IJOOH OH I ZOHaOH g 3 'CIIOOH .OOOCH:

COOCH! Diethyl 3 hydroxy 2 phenylquinoline 4,8 dicarboxylate One gm. of 3-hydroxy-2-phenylquinoline-4,8-.dicarboxylic acid -(-.003-mo1e) was added to a dry ml. Erlenmeyer flask containing 15 ccof absolute ethanol (.3 mole) and .5 cc. of concentrated sulfuric acid. The solution was then refluxed on a steam bath for 6 hours and cooled. To the dark brown solution was added 30 ml. of cold water, giving an immediate solid oily layer and some .yellowprecipitate. The yellow precipii816 disappeared upon the-addition of ammonium hydroxide which gave the solution a pH of 11. Extraction of the solution with three 25 cc. portions of ether then fellowed. The drying of the ethereal solution was accomplished over anhydrous potassium carbonate for '30 minutes. 'The solution was decanted,an'd the'ether evaporated on a hot water bath to a volume of 10 m1. (54.6% of theoretical). .After standing overnight, the solution gave 16 g. of 'long rectangular :dark yellow 1crystals which'melted'at 121.0 C., corrected.

. Analysis.Calcu1atedfor Gail-119N105:

Theory: Found:

C=69.03% C=69.21% H=5.20% H=5.04%

+2CH3CH2OH N Q OOH (IEOOOHrOHa Preparation of Di n-pr0pyl-3 hydr0xy-2-phenylquin0line- 4,8-dicarb0xylate To a 125 ml. dryErlenmeyer flask containing 1 gm. of 3-hydroxy-2-phenylquinoline-4,8-dicarboxylic vacid (.003 mole) was added 15 cc. of redistilled n-propanol (.3 mole) and .6 cc. of concentrated sulfuric acid. The solution was then refluxed 7 hours under a steam bath and then cooled. Dilution of the solution was effected by 30 ml. of cold water, which produced some yellow precipitate. However, when the solution was made alkaline with ammonium hydroxide, the yellow precipitate dissolved. Extraction was accomplished with three 25 ml. portions of ether and the extract was washed with ml. of water. The ether solution was dried over anhydrous potassium carbonate for 30 minutes and decanted into a beaker and evaporated over a hot water bath to a volume of 20 ml. The solution was allowed to lay overnight, but only dark oily droplets formed. Thus, the oily droplets and solution were dissolved in 10 ml. of ethanol, and treated with 1 gm. Darco (decolorizing charcoal). The solution was filtered and the filtrate was left standing overnight. Inasmuch as no crystals settled out of the dark brown solution, some water was added until a slight turbidity formed. The solution was stirred for several minutes and allowed to lay overnight. Next day .5 gm. (41.6% of theoretical) of long light yellow crystals formed, which melted at 86.5-87.0 C., corrected.

Q zcmcnicnion C O O CHzOHzCH:

O O CHQCHaCH:

Preparation of n-dibutyl-3-hydr0xy-2phenylquinoline-4,8- dicarboxylate One gm. of 3-hydroxy-2-phenylquinoline-4,S-dicarboxylic acid (.003 mole) was added to a dry 125 ml. Erlenmeyer flask containing ml. of n-butanol (.25 mole) and .6 ml. of concentrated sulfuric acid. The solution was then refluxed on the steam bath for 10 hours and cooled. To the dark brown solution was added 30 ml. of cold water and then concentrated ammonium hydroxide until the pH was about 11. Extraction of the solution with three 25 ml. portions of ether then followed. The ethereal solution was then dried over anhydrous potassium carbonate for 30 minutes and then decanted into a 300 ml. beaker. The solution was evaporated to a volume of ml. and left standing overnight, which gave a thick viscous oily residue. Since the viscous material was due to possibly tarry material, the oily residue was dissolved in 20 cc. of ethanol and treated with 1 g. of Darco charcoal. The solution was filtered, and 3 ml. of water was added, which gave a heavy yellow turbidity. The solution was allowed to stand overnight, but only an oily layer formed. The solution and oily layer were then dissolved in 10 ml. n-butanol and again treated with 1 gm. of activated charcoal (Darco). A clear filtrate resulted and this solution was then diluted with 3 cc. of ethyl alcohol stirred for several minutes and allowed to stand. After 3 days, .6 gm. (46.1% of theoretical) of long lemon yellow crystals formed, which melted at 59.5-60.0 C., corrected.

12 Analysis.Calculated for C25H21N1O5:

Theory: C=71.21% Found: C=7l.39%

H=6.46% H=6.56% N=3.32% N==3.18%

ZCHICHICHICHiOH s Q 00 0 CHICHICHICH! o o 0 CHICHlCHICHI Preparation of silver-3-hydr0xy-2-phenylquinoIine-4,8-dicarboxylate Into a 200 ml. beaker containing 40 ml. of water was placed 1 gm. of 3-hydroxy-2-phenylquinoline-4-8-dicarboxylic acid (.003 m.). Then a solution of 1 cc. of concentrated ammonium hydroxide dissolved in 30 cc. of water was added to the suspended acid giving a pH of 7 to the solution. The solid acid dissolved immediately, except for a slight trace of yellow precipitate which was then filtered off. To the solution was then added .3 gm. of silver nitrate dissolved in 30 cc. of water. A heavy yellow precipitate formed, which was filtered and washed with water. The filtrate was tested with dilute hydrochloric acid, and the washing ceased when the hydrochloric acid gave a negative test for silver. The silver salt was dried in the drak in a desiccator over sulfuric acid. The yield was 1.1 gm. (64.7% of theoretical) of dry dark brown crystals which did not melt under 315 C.

Analysis.Calculated for C17H9O5N1Agz:

Theory: C=38.04% Found: C=38.17% H: 1.73 H=1.80% Ag=4l.26% Ag=4l.3l%

Preparation of 3-hydr0xy-2-phenylquin0line The decarboxylation of 3-hydroxy-2-phenylcinchoninic acid was accomplished quite easily by using the method of Dilthey and Thelen (Ben, vol. 58B (1925), p. 1588-9). To 10 gm. of 3-hydroxy-2-phenylcinchoninic acid contained in a ml. Erlenmeyer flask, was added 30 ml. of nitrobenzene. The flask under reflux, was then heated by a direct flame for 3 hours. The volume of the nitrobenzene solution was brought down to about 15 cc. by heating on a hot plate near a hood. A tan precipitate crystallized out and was filtered giving 6.1 gm. of solid. The melting point of the alkali soluble 3-hydroxy-2- phenylquinoline was found to be 223 C. Dilthey and Thelen gave a melting point of 220 C., while Bargellini and Berlingozzi (Gazz. Chim. ItaL, vol. 53 (1923), p. 3) reported 221-222" C. and Henze and co-workers (I. A. C. 8., vol. 70, (1948), pp. 2622-4) 228 C. The picrate of 3-hydroxy-2-phenylquinoline was thus prepared and gave a melting point of 238 C. with decomposition. This melting point agreed with that given by Bargellini who gave a range of 23538 C., while Henze gave a melting point of 245 C., which was slightly higher. Preparation of carbamates of 3-hydr0xy-2-phenylquin0- line PREPARATION OF 2-PHENYLQUINOLINE--PHENYL- CARBAMATE To a dry 9 x /2 inch Pyrex test tube was added .5 gm. of 3-hydroxy-2-phenylquinoline and .5 ml. of phenylisocyanate. The liquid phenylisocyanate however, only seemed to moisten the hydroxy compound. Therefore, 5 ml. of dry benzene was added to the test tube, and the solution was heated on a steam bath, protected with a calcium chloride tube. The reaction did not seem to go, in that the compound did not dissolve, so 2 drops of pyridine were added to act as catalyst. The solution was heated for another minutes, and cooled. The benzene solution, with its solid residue was dissolved in 30 ml. of benzene and filtered. A slight amount of white solid remained whose melting point was 233 C. This was probably diphenyl urea, melting point 238 C. The benzene filtrate was evaporated to about 8 cc. and a gray solid precipitated, melting point 16270. Since the compound was quite obviously contaminated, the solid was dissolved in 25 cc. of carbon tetrachloride assuming that if the impurity were diphenyl urea, it would be insoluble in carbon tetrachloride and so separated. The solution was filtered from a slight amount of residue and the filtrate was evaporated to dryness. The residue was then dissolved in 20 ml. of ethyl acetate and fine white crystals formed when ml. of petroleum ether was added. .2 gm. of product was isolated melting at 162.0 C., corrected.

Analysis.Calculated for C22H16N2O2:

Theory: C=77.61% Found: C=77.48% H=4.74% H=4.59% N=8.24% N=8.34%

Preparation of 2-phenylquinoline-3-(1 naphthylcarbamate) Inasmuch as the phenol was not too soluble in carbon tetrachloride, benzene or ligroin, .5 gm. of 3-hydroxy-2- phenylquinoline and .5 cc. of alpha-naphthyl isocyanate were heated directly by a low flame in a dry 9 x /2 inch Pyrex test tube. Previous to heating, 2 drops of pyridine had been added to act as a catalyst. This heating operation was performed so as to eifect reaction, since a water bath had proved completely inadequate. The Pyrex test tube was taken away from the flame as soon as solution was efiected, and left at room temperature, sealed by a rubber cork. As soon as the dark liquid solidified the heating was repeated until liquid again. This operation was repeated several times. The dark residue was then dissolved in 10 m1. of carbon tetrachloride, giving a dark brown solution. Evaporation of the solution to 4 ml. gave a tan crystalline product. The product was dissolved in ml. of carbon tetrachloride and filtered. The volume was evaporated to 10 ml., and 5 ml. of petroleum ether was added. Immediate turbidity resulted, and after several hours, a light tan product (.3 g.) was filtered and recovered, melting point 143-4 C.

Analysis.-Calculated for CzsHlaNzOz:

Theory: Found:

C=79.97% C=79.95% H=4.65 H=4.85 N=7.l7% =7.20%

scam

14 Preparation of 2-phenylquin0line-3-(2 naphthyl carbamate) To .5 gm. of 3-hydroxy-2-phenylquinoline was added .5 gm. of beta-naphthyl-isocyanate contained in a /2 X 9 inch dry Pyrex test tube. The solid mixture was heated directly over a low flame until the solids melted. The flame was taken away, and the test tube stoppered. Within a few minutes the liquid melt solidified. The test tube was again heated until the solid melted, and then the flame was taken away. The dark brown melt was dissolved in ethyl acetate and filtered from a slight amount of white residue. Evaporation of the ethyl acetate filtrate to 30 ml. was then accomplished on a hot plate and the solution cooled. Petroleum ether was added until crystallization began, and the solution was allowed to stand several hours. Light tan crystals formed, which were filtered, giving .8 gm. of product melting at 181.0-5 C.

Analysis.-Calculated for CzsHtsNzOz:

Accordingly, it is believed that derivatives have been synthesized having antidiuretic properties and it is thought that the foregoing objects have been fulfilled.

I claim:

1. An antidiuretic having the structural formula:

wherein Z is selected from the group consisting of:

NH magi) And 2. 2-phenylquinoline-3-phenylcarbamate. 3. 2-phenylquinoline-3-( l-naphthylcarbamate). 4. 2-phenylquinoline-3-(Z-naphthylcarbamate).

References Cited in the file of this patent UNITED STATES PATENTS 1,773,837 Wolfienstein Aug. 26, 1930 

1. AN ANTIDIURETIC HAVING THE STRUCTURAL FORMULA: 